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Nucleic Acids Res. 2018 Jun 20;46(11):5504-5524. doi: 10.1093/nar/gky263.

A novel long non-coding RNA from NBL2 pericentromeric macrosatellite forms a perinucleolar aggregate structure in colon cancer.

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Program of Predictive and Personalized Medicine of Cancer (PMPPC), Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, Ctra Can Ruti, camí de les escoles s/n, Badalona, Barcelona 08916, Spain.
Institute for Research in Biomedicine (IRB Barcelona), Parc Científic de Barcelona, Carrer de Baldiri Reixac, 10-12, Barcelona 08028, Spain.
Active Motif, 1914 Palomar Oaks Way, Suite 150, Carlsbad, CA 92008, USA.
Division of RNA Biology & Cancer, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
Division of Cancer Research, Dept. of Thoracic Surgery, Medical Center - University of Freiburg & Faculty of Medicine, University of Freiburg & German Cancer Consortium (DKTK), Freiburg, Germany.
Josep Carreras Leukaemia Research Institute (IJC), Campus ICO - Germans Trias i Pujol, Campus Can Ruti, Badalona, Barcelona 08916, Spain.
Sanford-Burnham-Prebys Medical Discovery Institute (SBP), 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Department of Pathology and Experimental Therapeutics, School of Medicine and Health Sciences, Campus of Bellvitge, University of Barcelona, Carrer de la Feixa Llarga, s/n, L'Hospitalet de Llobregat, Barcelona 08907, Spain.


Primate-specific NBL2 macrosatellite is hypomethylated in several types of tumors, yet the consequences of this DNA hypomethylation remain unknown. We show that NBL2 conserved repeats are close to the centromeres of most acrocentric chromosomes. NBL2 associates with the perinucleolar region and undergoes severe demethylation in a subset of colorectal cancer (CRC). Upon DNA hypomethylation and histone acetylation, NBL2 repeats are transcribed in tumor cell lines and primary CRCs. NBL2 monomers exhibit promoter activity, and are contained within novel, non-polyA antisense lncRNAs, which we designated TNBL (Tumor-associated NBL2 transcript). TNBL is stable throughout the mitotic cycle, and in interphase nuclei preferentially forms a perinucleolar aggregate in the proximity of a subset of NBL2 loci. TNBL aggregates interact with the SAM68 perinucleolar body in a mirror-image cancer specific perinucleolar structure. TNBL binds with high affinity to several proteins involved in nuclear functions and RNA metabolism, such as CELF1 and NPM1. Our data unveil novel DNA and RNA structural features of a non-coding macrosatellite frequently altered in cancer.

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